Objective Infections contribute to morbidity and mortality in systemic lupus erythematosus (SLE). Uropathogenic Escherichia coli (UPEC) are known to trigger urinary tract infections (UTIs) and form biofilms, which are multicellular communities of bacteria that are strengthened by amyloids such as curli. We previously reported that curli naturally form complexes with bacterial extracellular DNA (eDNA), and these curli/eDNA complexes induce hallmark features of lupus in mouse models. The present study was undertaken to investigate whether anti–curli/eDNA complex antibodies play a role in the pathogenesis of SLE or development of flares in SLE. Methods In total, 96 SLE patients who met at least 4 Systemic Lupus International Collaborating Clinics disease criteria were investigated. Anti–curli/eDNA complex antibodies in the plasma were tested for both IgG and IgA subclasses. Results were compared to that in 54 age‐, sex‐, and race/ethnicity‐matched healthy controls. Correlations of the levels of anti‐curli/eDNA antibodies with clinical parameters, lupus disease status, and frequency of bacteriuria were assessed. Results Anti‐curli/eDNA antibodies were detected in the plasma of SLE patients and healthy controls, and their levels correlated with the presence of asymptomatic persistent bacteriuria and occurrence of disease flares in lupus patients. Persistent bacteriuria contained curli‐producing UPEC, and this was associated with an inflammatory phenotype. Finally, curli/eDNA complexes cross‐reacted with lupus autoantigens, such as double‐stranded DNA, in binding autoantibodies. Conclusion These results suggest that UTIs and persistent bacteriuria are environmental triggers of lupus and its flares. Antibodies against curli/eDNA could serve as a sign of systemic exposure to bacterial products in SLE.

The circadian clock controls daily activities at the cellular and organismic level, allowing an organism to anticipate incoming stresses and to use resources accordingly. The circadian clock has therefore been considered a fitness trait in multiple organisms. However, the mechanism of how circadian clock variation influences organismal reproductive fitness is still not well understood. Here we describe habitat-specific clock variation (HSCV) of asexual reproduction in Neurospora discreta, a species that is adapted to 2 different habitats, under or above tree bark. African (AF) N. discreta strains, whose habitat is above the tree bark in light-dark (LD) conditions, display a higher rhythmicity index compared with North American (NA) strains, whose habitat is under the tree bark in constant dark (DD). Although AF-type strains demonstrated an overall fitness advantage under LD and DD conditions, NA-type strains exhibit a habitat-specific fitness advantage in DD over the LD condition. In addition, we show that allelic variation of the clock-controlled gene, Ubiquinol cytochrome c oxidoreductase (NEUDI_158280), plays a role in HSCV by modulating cellular reactive oxygen species levels. Our results demonstrate a mechanism by which local adaptation involving circadian clock regulation influences reproductive fitness.

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Infections are a major contributor to lupus disease. We have previously demonstrated that bacterial amyloid curli, produced by E.coli, can accelerate disease in mouse models of lupus. Interestingly curli incorporates extracellular DNA, which in turn can be both adjuvant and a self-antigen in lupus. Finally, uropathogenic E. coli (UPEC) is responsible for the majority of urinary tract infections in SLE. Based on our previous results, we hypothesize that exposure to UPEC triggers anti-curli antibodies, and that curli can also trigger the innate immune system. We investigated 34 lupus patients who met at least 4 SLICC criteria. Results were compared to 17 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex for both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters, including anti-dsDNA antibodies and bacteriuria. Finally, we used curli/DNA complexes to stimulate PBMCs from lupus patients and controls and determined the levels by rt-PCR of IL-6 (bacterial response) and MX-1 (type I interferon (IFN I) activation). We found that lupus patients and healthy controls generated anti-curli antibodies of IgG and IgA subclasses. The levels of anti-curli antibodies significantly correlated with the levels of anti-dsDNA antibodies (p=0.029) and persistent bacteriuria (p=0.035) in lupus patients. Finally we found that curli/DNA complexes triggered production of IL-6 and MX-1 in both healthy and lupus PBMCs. Nevertheless, the expression of MX-1 was significantly higher in PBMCs from lupus patients (p=0.012). Our results show that bacterial curli/DNA is a trigger of systemic autoimmunity via activation of IFN I and production of autoantibodies.

Figure 2 A-B: Placentas from Sle1 (A) and Sle1.huTLR8 (B) term pregnancies showing the width of the decidua (blue bar) and junctional zone (yellow bar). C: Junctional zone width in placentas from transgenic mice and controls -red indicates resorbed or dead pups. D: Placental weight at Days 8.5 and 13.5